WO2011018801A2

WO2011018801A2 - Solid oral dosage form of ziprasidone

Info

Publication number: WO2011018801A2
Application number: PCT/IN2010/000537
Authority: WO
Inventors: Deepak Murpani; Pandora Alexaki
Original assignee: Genepharm India Pvt Ltd
Priority date: 2009-08-12
Filing date: 2010-08-12
Publication date: 2011-02-17
Also published as: WO2011018801A3

Abstract

A solid oral dosage form comprising ziprasidone or its pharmaceutically acceptable salt and cationic ion exchange resin and the process of its preparation.

Description

SOLID ORAL DOSAGE FORM OF ZIPRASIDONE

The present invention relates to a solid oral dosage form of an antipsychotic agent, 5-[2-[4-( ] ,2-benzisothiazol 3-yl)-1 - piperazinyl]ethyl] -6- chloro -1,3-dihydro 2H - indol -2-one or ziprasidone (INN name) and its pharmaceutically acceptable salt(s). Ziprasidone and its pharmaceutically acceptable salts are indicated for the treatment of schizophrenia.

BACKGROUND OF THE INVENTION

United States patent Number 4,831,031 and 5,312,925 (assigned to M/S Pfizer, referred to herein as '031 and '925) disclose ziprasidone. The '925 patent specifically discloses ziprasidone hydrochloride monohydrate which is the active ingredient in the commercial product. The '031 patent describes that ziprasidone can be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension for oral use. In the case of tablets or capsules for oral use, carriers which may be used include lactose and corn starch. Ziprasidone capsule contains a monohydrochloride, monohydrate of ziprasidone. Ziprasidone capsules are commercially available from Pfizer under the trademark Geodon capsules and contain ziprasidone monohydrochloride monohydrate, lactose, pre-gelatinized starch and magnesium stearate.

The '031 patent does not exemplify a solid oral dosage form of ziprasidone or its pharmaceutically acceptable salts. United States Patent Number 6150336 (assigned to M/s Pfizer referred to herein as '366 patent) exemplifies ziprasidone hydrochloride capsules containing 20 mg activity wherein mean particle size (VMD) of ziprasidone hydrochloride is either 20, 84 or 105 micron. The excipients used in these capsules are lactose monohydrate, pregelatinized maize starch magnesium stearate. The '366 patent suggests micronisation of ziprasidone to improve bioavaibility. However, micronisation is economically unviable and a cumbersome process on commercial scale. PCT publication No. 2005107719 (assigned to M/S Sandoz) discloses the use of citric acid to improve solubility of hydrophobic drug such as ziprasidone.

PCT publication No. 2005/065660 (assigned to M/S Alpharma referred to herein as '660 publication) discloses amorphous ziprasidone dihydrochloride dihydrate tablets with polyvinylpyrrolidone, wherein the preferred mean particle size of ziprasidone dihydrochloride dihydrate is about 88 to 150 microns. The '660 publication does not suggest use of ziprasidone hydrochloride monohydrate and ion exchange resin for the manufacture of tablets, wherein the mean particle diameter of ziprasidone hydrochloride monohydrate may vary from 50 to 500 microns.

The present invention provides solid oral dosage form of ziprasidone wherein ziprasidone will be in a stable amorphous form. The oral dosage form of ziprasidone or its pharmaceutically acceptable obviates the need for micronisation to improve bioavaibility. The rate of release of ziprasidone can be controlled irrespective of the particle size. The solid oral dosage form of ziprasidone or its pharmaceutically acceptable salt of the present invention will consistently provide stable amorphous ziprasidone.

OBJECT OF THE INVENTION

The object of the present invention is to provide a solid oral dosage form of ziprasidone comprising ziprasidone or its pharmaceutically acceptable salt and cationic ion exchange resin & the process of its preparation. More specifically, the present invention provides solid oral dosage form of ziprasidone comprising ziprasidone or its pharmaceutically acceptable salt and cationic ion exchange resin wherein ziprasidone is in stable amorphous form.

The process for the preparation of solid oral dosage form of ziprasidone of the present invention comprises a) dispersing/dissolving ziprasidone or its pharmaceutically acceptable salt in water;

b) adding cationic ion exchange resin to a) with constant stirring with or without heat to prepare ziprasidone resinate;

c) optionally adding pharmaceutical excipients; and

d) formulating into tablets or pellets or powder / filling in capsules.

5. DESCRIPTION OF THE INVENTION

The present invention provides a solid oral dosage form of ziprasidone comprising ziprasidone or its pharmaceutically acceptable salt and a cationic ion exchange resin. 0 According to one^; embodiment of the present invention the solid oral dosage form of ziprasidone comprises ziprasidone or its pharmaceutically acceptable salt and cationic ion exchange resin, wherein ziprasidone is in stable amorphous form.

Ziprasidone or its pharmaceutically acceptable salt used in the present invention may be in crystalline or5 amorphous form and the mean particle diameter may vary from 50 to 500 microns.

The Cationic ion exchange resin used in the present invention may be selected from

(a) the cationic (strongly acidic) ion exchange resin Amberlite Resin Grade IRP-69 (a trade name of

Rohm and Haas Company) wherein sodium ion is the exchange cation.

0 (b) the cationic (weakly acidic) ion exchange resin Amberlite Resin Grade IRP-64 (a trade name of

Rohm and Haas Company for a brand of polacrilex resin; herein after generally referred to as IRP-64) wherein hydrogen ion is the exchange cation. The INN name is polacrilex resin. Polacrilex resin is the methacrylic acid polymer with divinylbenzene.

(c) the cationic (weakly acidic) ion exchange resin Amberlite Resin Grade IRP-88 (a trade name of5 Rohm and Haas Company) wherein potassium ion is the exchange cation. The INN name is polacrilin potassium. Polacrilin potassium is the potassium salt of polacrilex resin.

More specifically, the present invention provides a pharmaceutical composition for oral administration comprising ziprasidone or pharmaceutically acceptable salt thereof, and an effective amount of cationic ion0 exchange resin wherein the weight ratio of ziprasidone or pharmaceutically acceptable salt thereof to cationic ion exchange resin is 1 :1 to 1 :6.

On formation of the ziprasidone resinate, additional excipients may be added such as fillers, binders, compression aids, disintegrants, glidants, lubricants, flavouring agents, water scavengers, colorants,5 sweetening agents, coating agents and preservatives. Although the pharmaceutical composition may be in various forms, the preferred solid forms are tablets, oral dispersible tablets, soluble tablets, water dispersible tablets, sprinkles, chewable tablets, effervescent tablets, orally disintegrating tablets, powder for suspension, capsules, sachets and caplets. The preferred pharmaceutical compositions of ziprasidone or pharmaceutically acceptable salt thereof are in the form of solid dosage forms such as orally disintegrating tablets and the like, in all shapes and sizes, coated or uncoated.

The present invention provides a solid dosage formulation for oral administration containing ziprasidone or pharmaceutically acceptable salts thereof, is effective with sufficient shelf-life, good pharmacotechnical properties and bioavailability of ziprasidone. The improved solid pharmaceutical composition of the present invention is characterized by physicochemical properties suitable for the tablet formulation by wet granulation, so as to obtain adequate release rate of ziprasidone. Another essential advantage of the present invention is that the solid dosage form according to the present invention ensures excellent stability and bioavailability of the active ingredient. The manufacturing process for preparation according to the present invention is simpler and inexpensive in comparison to any other conventional method.

The pharmaceutical excipient may be selected from diluents, binders, lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, surfactants, glidants, plasticizers, preservatives and sweeteners.

According to another embodiment of the present invention, a taste masked dosage form of ziprasidone or its pharmaceutically acceptable salt may comprise coating non-pareil seeds or inert granules with a mixture of ziprasidone or its pharmaceutically acceptable salt, cationic polymer, an optional polymer and atleast one pharmaceutical excipient.

The non-pareil seeds or inert granules may be selected from water soluble and water insoluble non-fine particles such as directly compressible dibasic calcium phosphate, microcrystalline cellulose, directly compressible sugar such as directly compressible mannitol commercially available as PEARLITOL, starch and the like.

The cationic polymer is polymers with dimethylaminoethyl groups such as Eudragit® E-IOO and Eudragit ® EPO. Eudragit E is a cationic polymer based on dimethylaminoethyl methacrylate and neutral methacrylates. It is soluble in gastric fluid as well as in weakly acidic buffer solutions (upto about pH 5). The optional polymer may be selected from ethylcellulose, cellulose acetate, hydroxypropyl-methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and the like. The pharmaceutical excipient must be compatible with ziprasidone or its pharmaceutically acceptable salt. The pharmaceutical excipient is selected from diluents, binder's lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, surfactants, glidants, plasticizers, preservatives and sweeteners.

Diluents may be selected from calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol sorbitol, starch, pregelatinized starch, sucrose, talc,xylitol,maltose maltodextrin, maltitol.

Binders may be selected from acacia, alginic acid, carbomer, carboxymethylcellulose calcium, carbomethylcellulose sodium, microcrystalline cellulose,powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl ceJlulos, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, methylcellulose, ploydextrose, polyethtylene oxide,povidone, sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose,glucose, sorbitol. Suitable fillers are preferably selected from atleast one of starch derivatives,such as corn starch, potato starch or rice starch. Polysaccharides such as dextrins, maltodextrins, dextrates, microcrystalline cellulose, powdered cellulose, mixture of microcrystalline cellulose and guar gum, coprocessed blends of microcrystalline cellulose; and polyhydric alcohols, such as xylitol and sorbitol.

Disintegrants may be selected from, alginic acid, carbon dioxide, carboxymethylcellulose, calcium carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gaur gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium , poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium laulyl sulfate, sodium starch glycolate, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose. Glidants may be, for example, calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide.

Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, and glyceryl behenate. Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; and aspartame. Flavoring agents may be selected from natural or synthetic flavors such as strawberry flavor, wild cherry flavor, green apple flavor, spearmint flavor and peppermint flavor.

In one another embodiment of the present invention the process for the preparation of taste masked resinate or taste masked granules or taste masked dosage form of ziprasidone or its pharmaceutically acceptable salt is also provided.

A process for the preparation of solid oral dosage form of ziprasidone comprising

a. dispersing / dissolving crystalline or amorphous ziprasidone or its pharmaceutically acceptable salt in water;

b. adding cationic ion exchange resin to (a) with constant stirring with or without heat to prepare ziprasidone resinate;

c. optionally adding pharmaceutical excipient; and

d. formulating into tablets or pellets or powder/filling in capsules. More specifically, a process for the preparation of solid oral dosage form of ziprasidone in stable amorphous form comprising

a. dispersing / dissolving crystalline or amorphous ziprasidone or its pharmaceutically acceptable salt with a mean particle diameter of 50 to 500 microns in water;

c. optionally adding pharmaceutical excipient; and

d. formulating into tablets or pellets or powder/filling in capsules.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope of the invention.

5 EXAMPLES

Example 1: Preparation of resinate of ziprasidone

Dissolve / disperse ziprasidone hydrochloride monohydrate in purified water with the aid of stirring with or ) without heat to form dispersion. Disperse 1-4 wt parts of cationic ion exchange resin 1RP69 to the solution/dispersion of ziprasidone hydrochloride monohydrate with constant stirring. The pH of solution is adjusted with dilute HCl to pH 3±1, stir with or without heating to obtain the resinate. Filter the resinate slurry and keep the resinate for drying. Example 2: Preparation of ziprasidone capsules of 80 mg strengths (1 :1 resinate)

Resinate of 1 wt part of ziprasidone hydrochloride monohydrate (equivalent to 80 mg of ziprasidone) with 1 wt part of IRP 69 is 1. sifted through suitable sieved BSS and

2. appropriate quantity of powder is filled into suitable capsule shells

Example 3: Preparation of ziprasidone capsules of 80 mg strengths (1:2 resinate) Resinate of I wt part of ziprasidone hydrochloride monohydrate (equivalent to 80 mg of ziprasidone) with 2 wt part of IRP 69 is

1. sifted through suitable sieved BSS and

2. appropriate quantity of powder is filled into suitable capsule shells.

Example 4: Preparation of ziprasidone capsules of 80 mg strengths (1:3 resinate)

Resinate of 1 wt part of ziprasidone hydrochloride monohydrate (equivalent to 80 mg of ziprasidone) with 3 wt part ofIRP 69 is

1. sifted through suitable sieve# BSS and

2. appropriate quantity of powder is filled into suitable capsule shells.

Example 5: Preparation of ziprasidone capsules of 80 mg strengths (1:4 resinate)

Resinate of 1 wt part of ziprasidone hydrochloride monohydrate (equivalent to 80 mg of ziprasidone) with 4 wt part ofIRP 69 is

1. sifted through suitable sieve# BSS and

2. appropriate quantity of powder is filled into suitable capsule shells. Example 6: Preparation of resinate of ziprasidone

Dissolve / disperse ziprasidone hydrochloride monohydrate in purified water with the aid of stirring with or without heat to form dispersion. Disperse 4 parts of ion exchange resin IRP88 to the solution/dispersion of ziprasidone hydrochloride monohydrate with constant stirring. The pH of solution is adjusted with dilute HCI to pH 2.5±2, stir with or without heating to obtain the resinate. Filter the resinate slurry and keep the resinate for drying.

Example 7: Preparation of ziprasidone capsules of 80 mg strengths (1:4 resinate) Resinate of 1 wt part of ziprasidone hydrochloride monohydrate (equivalent to 80 mg of ziprasidone) with

4 wt part of IRP 88 is

1. sifted through suitable sieve# BSS and

2. appropriate quantity of powder is filled into suitable capsule shells.

Example 8: Preparation of ziprasidone capsules of 40 mg strengths (1:4 resinate)

Resinate of 1 wt part of ziprasidone hydrochloride monohydrate (equivalent to 40 mg of ziprasidone) with 4 wt part ofIRP 88 is

1. sifted through suitable sieve# BSS and

2. appropriate quantity of powder is filled into suitable capsule shells.

Example 9: Dissolution Studies

Claims

We claim:

1 A solid oral dosage forms comprising ziprasidone or its pharmaceutically acceptable salt, cationic ion exchange resin and optionally pharmaceutical excipient(s).

2. A solid oral dosage form as claimed in claim 1 wherein ziprasidone or its pharmaceutically acceptable salt is crystalline or amorphous.

3. A solid oral dosage form as claimed in claim 1 wherein the weight ratio of ziprasidone or its pharmaceutically acceptable salt to cationic ion exchange resin is 1 :1 to 1: 6.

4. A solid oral dosage form as claimed in claim 1 in stable amorphous form.

5. A solid oral dosage form as claimed in claim 1 wherein the mean particle diameter of ziprasidone or its pharmaceutically acceptable salt is 50 to 500 microns.

6. A solid oral dosage form as claimed in claim 1 in stable amorphous form whereirf the mean particle diameter of ziprasidone or its pharmaceutically acceptable salt is 50 to 500 microns.

7. A solid oral dosage form as claimed in claim 2 in stable amorphous form wherein the mean particle diameter of ziprasidone or its pharmaceutically acceptable salt is 50 to 500 microns.

8. A process for the preparation of solid oral dosage form of ziprasidone comprising

a. dispersing/dissolving crystalline or amorphous ziprasidone or its pharmaceutically acceptable salt in water;

c. optionally adding pharmaceutical excipient; and

d. formulating into tablets or pellets or powder/filling in capsules.

9. A process for the preparation of solid oral dosage form of ziprasidone in stable amorphous form comprising

a. dispersing/dissolving crystalline or amorphous ziprasidone or its pharmaceutically acceptable salt with a mean particle diameter of 50 to 500 microns in water; b. adding cationic ion exchange resin to (a) with constant stirring with or without heat to prepare ziprasidone resinate;

c. optionally adding pharmaceutical excipient; and

d. formulating into tablets or pellets or powder/filling in capsules.

10. A process as claimed in claim 8 or 9 wherein the weight ratio of ziprasidone or its pharmaceutically acceptable salt to cationic ion exchange resin is 1 : 1 to 1 : 6.